1. Field of the Invention
The present invention relates to an agent for preventing and treating cancer comprising an oxadiazole urea compound as an effective ingredient, the agent effectively inhibiting the growth of a cancer cell line and STAT3 activity.
2. Description of the Related Art
Although the incidence of cancer is increasing with the advance of civilization, the treatment of cancer patients depends on surgery, radiotherapy, and chemotherapy, involving the administration of about forty anticancer substances having high cytotoxicity. Since these therapies are mostly limited to early cancer patients or specific cancer types, cancer death rates are increasing.
Cancer is the most incurable disease, and mechanisms of cancer incidence and progress are similar to those of vascular diseases, rheumatoid arthritis and other immunological diseases. In this regard, many studies involving anticancer agents have been performed. Selective anticancer agents, which act on specific molecular targets, are gaining more attention because they provide safer and more effective strategies and are applicable in personalized medicine and combination therapy.
Signal transducers and activators of transcription (STAT) proteins (STAT1, STAT2, STAT3, STAT4, STAT5 and STAT6), which have a molecular weight ranging from 84 to 113 kDa, contain an SH2 domain, which recognizes one or more phosphotyrosines present in the cytoplasmic domains of some activated receptors.
The SH2 (Src Homology-2) domain serves as a phosphorylation-dependent switch to control receptor recognition and DNA binding. Thus, STAT proteins enable the direct linkage of the activity of cell surface receptors to gene regulation (James R. Darnell, Jr., Proceedings of the National Academy of Sciences. USA, 94, 11767-11769, (1997)).
In animal cells, activation of the latent cytoplasmic STAT molecules is accomplished either through cell surface receptors for cytokines and their non-covalently-associated Jak kinases or by growth factor receptors having intrinsic tyrosine kinase activity.
Binding of the cognate ligand to the cell surface receptor causes the phosphorylation of tyrosines in the cytoplasmic regions of the receptor, thereby creating docking sites for the STAT SH2 domain. The consequent recruitment of the STATs to the receptor leads, in turn, to their phosphorylation on tyrosine by the Jak or receptor kinases. The phosphorylated STATs form SH2-mediated dimers and are then translocated to the nucleus, where they bind to DNA and direct specific transcriptional initiation.
STAT signaling is assumed to be terminated by dephosphorylation and proteolytic degradation.
Constitutive activation of STAT proteins, in particular, STAT1, STAT3 and STAT5, is found in a wide variety of human cancers. In particular, STAT3 is activated in blood malignancies, such as leukemias, as well as solid tumors, such as breast cancer, head and neck cancer, melanoma, ovarian carcinoma, lung cancer, pancreatic carcinoma and prostate carcinoma. Thus, STAT3 is an important anticancer target (Hua Yu and Richard Jove, Nature Reviews Cancer (2004), 4, 97-105).
Blocking STAT3 function is important as a basic technique for developing more effective and substantial anticancer drugs by controlling tumors through multiple anticancer mechanisms involving apoptosis, angiogenesis inhibition and blocking of immune escape, and is expected to have high therapeutic effects compared to conventional anticancer drugs acting through a single mechanism Also, since STAT proteins participate in functions of various types of cells as well as in tumors, the development of STAT3 inhibitors may be utilized as a major basic technique having ripple effects on the development of immune suppressors and antidiabetic drugs.